Understanding the functional role of Myeloid Derived Suppressor cells in tuberculosis

项目总结。结核分枝杆菌(Mtb)，该病的病原体 结核病，据估计感染了世界四分之一的人口，导致大约 每年有160万人死亡。多重耐药和广泛耐药结核分枝杆菌菌株的出现 而目前使用的卡介苗(BCG)的可变效力是 阻碍全球结核病控制的障碍。因此，迫切需要更好地了解这些机制 结核病的免疫发病机制，因为这种机制可以针对改善宿主对结核分枝杆菌的控制 感染。长期以来，结节肉芽肿一直被认为是结核病的标志。我们公布的数据 提示含有诱导性支气管相关淋巴组织(IBALT)的存在 肉芽肿是一种保护性肉芽肿，在结核潜伏期间调节结核分枝杆菌的控制。在……里面 相反，浸润性髓系来源的抑制细胞(MDSCs)以及产生中性粒细胞 促炎分子是肺结核期间非保护性肉芽肿的特征。 MDSCs在人类、非人灵长类动物和小鼠的肺结核病期间被诱导 抑制保护性T细胞反应。我们的新数据显示对促炎性疾病有保护作用 细胞因子IL-17抑制肺MDSC蓄积和限制T细胞抑制 在肺结核期间的肺部。此外，我们还发现MDSC衍生的致炎蛋白， S100A8/A9异源二聚体是在人、NHP和小鼠感染结核分枝杆菌后诱导产生的。此外， 表达S100A8/A9的髓系细胞聚集在结节肉芽肿内并放大肺 MDSC积聚介导结核分枝杆菌易感性。在当前的提案中，使用鼠标和NHP ，我们将阐明调控和促进MDSC蓄积的机制(S) 并确定MDSCs及其通路是否可以作为宿主导向的靶点 结核病的治疗(HDTS)。在具体目标1中，利用基因缺陷和条件基因缺陷 小鼠模型，我们将确定IL-17依赖的途径，限制MDSC在 结核病。在特定的目标2中，我们将评估S100A8/A9蛋白在驱动MDSC聚集中的作用 以及对结核病的易感性，并确定阻断S100A8/A9信号是否会限制结核病 旧病复发。最后，在特定的目标3中，我们将评估MDSC耗尽是否可以防止结核病的进展 非人灵长类(NHP)。在完成这里提出的目标后，我们将有相当大的 扩大了我们对结核分枝杆菌特有的信号通路和因子的理解，这些信号通路和因子 (S100A8/A9通路)和负性(IL-17依赖通路)调节MDSC的聚集 在结核病期间。此外，我们在NHP中的翻译研究将使HDTS的使用能够限制MDSC 在结核病期间。

PROJECT SUMMARY. Mycobacterium tuberculosis (Mtb), the causative agent of the disease tuberculosis (TB), is estimated to infect one-fourth of the world's population, resulting in approximately 1.6 million deaths each year. The emergence of multidrug- and extensively drug-resistant Mtb strains and the variable efficacy of the currently used vaccine, M. bovis Bacille Calmette Guerin (BCG), are barriers to the global control of TB. Thus, there is a critical need to better understand the mechanisms of TB immunopathogenesis, as such mechanisms can be targeted to improve host control of Mtb infection. The tubercle granuloma is long been considered a hallmark of TB. Our published data suggest that the presence of inducible bronchus-associated lymphoid tissue (iBALT)-containing granulomas is indicative of protective granulomas that mediate Mtb control during TB latency. In contrast, infiltrating myeloid derived suppressor cells (MDSCs) as well as neutrophils producing proinflammatory molecules are characteristic of non-protective granulomas during pulmonary TB. MDSCs are induced during pulmonary TB in humans, nonhuman primates (NHPs) and mice and suppress protective T cell responses. Our new data show a protective role for the proinflammatory cytokine, Interleukin (IL)-17 in dampening lung MDSC accumulation and limiting T cell suppression in the lung during TB. Additionally, we show that the MDSC-derived proinflammatory proteins, S100A8/A9 heterodimers are induced upon Mtb infection in humans, NHPs and mice. Furthermore, S100A8/A9-expressing myeloid cells accumulate within the tubercle granuloma and amplify lung MDSC accumulation to mediate Mtb susceptibility. In the current proposal, using mouse and NHP models of TB, we will elucidate the mechanism(s) which regulate and promote MDSC accumulation during TB, and characterize whether MDSCs and their pathways can be targeted as host-directed therapeutics (HDTs) for TB. In Specific Aim 1, using gene deficient and conditional gene deficient mouse models we will determine the IL-17-dependent pathways that limit MDSC accumulation during TB. In Specific Aim 2, we will evaluate the role of S100A8/A9 proteins in driving MDSC accumulation and susceptibility to TB, and also determine whether blocking S100A8/A9 signaling will limit TB relapse. Finally, in Specific Aim 3 we will evaluate if MDSC depletion can prevent TB progression in nonhuman primates (NHPs). At the completion of the aims proposed here, we will have considerably expanded our understanding of the Mtb-specific signaling pathways and factors that positively (S100A8/A9 pathways) and negatively (IL-17 dependent pathways) regulate MDSC accumulation during TB. Additionally, our translational studies in NHPs will enable the use of HDTs to limit MDSCs during TB.